N-substituted nitroalkyl oxazolidine

ABSTRACT

N-Substituted nitroalkyl or nitrohydroxyalkyl oxazolidines having utility as anti-microbial agents.

BACKGOUND OF THE INVENTION

This invention relates to a method of controlling the growth of bacteria, fungi, algae and certain viruses. In a particular aspect this invention relates to a method of controlling the growth of bacteria, fungi, algae and viruses by applying thereto certain members of the class of oxazolidines.

Oxazolines have long been known in the art. They are readily prepared by reacting an amino alcohol with an aldehyde: ##STR1## If the amino alcohol is a diol and 2 moles of aldehyde are used, the resulting oxazolidine is bicyclic, as described by M. Senkus, J. Am. Chem. Soc. 67, 1515-1519 (1945) and Wm. B. Johnston, U.S. Pat. No. 2,448,890, which are incorporated herein by reference thereto: ##STR2##

It is an object of this invention to provide a method of controlling the growth of micro-organisms and certain viruses.

It is another object of this invention to control the growth of bacteria, fungi, algae and viruses by applying thereto certain members of the class of oxazolidines.

It is yet another object of this invention to provide novel oxazolidines.

Other objects of this invention will be apparent to those skilled in the art from the disclosure herein.

It has been discovered that the growth of many micro-organisms, i.e., bacteria, fungi, algae, and certain viruses is controlled by applying to these organisms an oxazolidine corresponding to formula I wherein R and R¹ can be hydrogen or alkyl of 1 or 2 carbons and can be the same or different; R² can be hydrogen or alkyl of from 1 to 3 carbon atoms, or the group represented by the formula: ##STR3## where R⁶ can be hydrogen, methyl, or ethyl and R⁷ can be methyl, hydroxymethyl, ethyl or the group ##STR4## or a bicyclic oxazolidine corresponding to formula II, where R⁴ can be hydrogen, alkyl of 1 or 2 carbon atoms, hydroxyalkyl, e.g. hydroxymethyl, or acyloxymethyl corresponding to the formula --CH₂ OOCR⁵ where R⁵ is an alkyl group of 1 or 2 carbon atoms R³ is hydrogen, alkyl of from 1 to 3 carbon atoms or hydroxyphenyl. The invention also contemplates a class of oxazolidine compounds believed to be novel wherein R² of formula I is nitroalkyl, viz., 2-nitro-2-methyl-1-propyl, 2-nitro-1-butyl or 2-nitro-1-propyl, or 2-nitro-1-ethyl, or nitrohydroxy alkyl.

DETAILED DESCRIPTION

Some of the oxazolidines used in the practice of this invention are commercially available and the usual commercial materials are suitable. 4,4-Dimethyl-1,3-oxazolidine is generally known as Oxazolidine A and this designation is employed in the examples. The bicyclic oxazolidine wherein R⁴ is ethyl is known as Oxazolidine E and this designation is used in the examples. The bicyclic oxazolidine wherein R⁴ is hydroxymethyl is known as Oxazolidine T and this designation is used in the examples. Other oxazolidines, i.e., esters thereof and those made from aldehydes other than formaldehyde, can be made by the method of M. Senkus or Wm. B. Johnston or J. A. Frump, U.S. Pat. No. 3,738,992.

When R² is nitroalkyl, the oxazolidines are prepared by condensing an oxazolidine represented by formula I with a nitroalkane and an aldehyde (or with a corresponding nitroalcohol), [viz.,] to produce compounds corresponding to the formula ##STR5## where R⁶ is hydrogen, methyl, or ethyl, and R⁷ is methyl, ethyl or hydroxymethyl, or R⁷ can be ##STR6## wherein R, R¹ and R³ have the same meaning as hereinbefore defined.

Most of these oxazolidines are water-soluble and are conveniently applied to the environment inhabited by micro-organism as a water solution. They are particularly effective in aqueous systems such as starch adhesives and solutions, drilling muds for the petroleum industry and in water-dilutable cutting oils based on petroleum hydrocarbons. A concentration of about 10-1000 μg/ml is required, but generally about 100-500 μg/ml is sufficient for all but the heaviest infestations.

These oxazolidines, especially the esters, are also soluble in, e.g., alcohols, ketones and most other organic solvents, including hydrocarbons. Solutions of the water-insoluble oxazolidines in such solvents can be used in substantially non-aqueous or 2-phase systems when desired.

A class of oxazolidines preferred for the practice of this invention is that wherein R² is represented by the formula ##STR7## wherein R⁶ and R⁷ have the same meanings as hereinbefore defined. These compounds, which are believed to be novel, are prepared by mixing one mole of a nitroalkane, e.g. nitroethane, 1-nitropropane or 2-nitropropane, with 1 or 2 moles of formaldehyde, then adding 1 or 2 moles of an oxazolidine corresponding to formula I wherein R² is hydrogen, preferably at an elevated temperature, e.g. 60°-70° C. The crude product is easily recovered by separating the water or solvent introduced with the formaldehyde (and also the water of reaction) by distillation.

The formaldehyde is preferably supplied as the 37% aqueous solution, but more concentrated solutions can also be used as is readily apparent. The formaldehyde can also be supplied as a solution in a lower alkanol, which solutions are commercially available, or as paraformaldehyde.

It is well-known in the art that nitroalkanes condense with one mole of formaldehyde to form a nitroalcohol, or with two moles of formaldehyde to form a nitro-alkanediol. It is believed that this reaction proceeds prior to or during the reaction with the oxazolidine. Hence nitrohydroxy compounds, which are commercially available, can be substituted for the nitroalkane and formaldehyde in the process and are regarded as the practical equivalents thereof.

The invention will be better understood by reference to the following examples. It is understood, however, that the examples are intended only for the purpose of illustration and it is not intended that the invention be limited thereby.

EXAMPLE 1

Oxazolidine A (4,4-dimethyl-1,3-oxazolidine) was tested by the Streak Plate Method, which is known in the art. The oxazolidine was incorporated into several portions of an agar medium at several known concentrations and the mixtures were placed in Petri dishes. Then streaks of test organisms were applied to the surface of the medium and the dishes were incubated under growth-promoting conditions, then examined for growth of organisms. The results are reported as a range, the lower figure signifying a concentration that allows growth and the upper being a concentration that inhibits growth.

The results are as follows:

    ______________________________________                                                           Inhibiting                                                                     Concentration                                                ______________________________________                                         BACTERIA                                                                       Staphylococcus aureus                                                                              100 - 500 μg/ml                                         Streptococcus fecalis                                                                              100 - 500                                                  Streptococeus hemolyticus                                                                          100 - 500                                                  Escherichia coli    100 - 500                                                  Pasteurella pseudotuberculosis                                                                      50 - 100                                                  Pseudomonas aeruginosa                                                                             100 - 500                                                  Shigella dysenteriae                                                                               100 - 500                                                  Mycobacterium tuberculosis                                                                         100 - 500                                                  FUNGI                                                                          A. niger            500 - 1000  μg/ml                                       Candida albicans    1000                                                       Penicillium species 500 - 1000                                                 A. fumigatus        100 - 500                                                  ALGAE                                                                          Six species of green and                                                                           19.5 - 156 μg/ml                                        blue-green                                                                     VIRUS                                                                          Newcastle's strain  100 - 1000 μg/ml                                        Boney-1 strain      100 - 1000                                                 ______________________________________                                    

EXAMPLE 2

A cutting oil emulsion was prepared according to the following formula:

    ______________________________________                                         Light mineral oil    20     parts                                              Water                74                                                        Oxazolidine A        3                                                         Mixed C.sub.18 Fatty Acids                                                                          3                                                                              100                                                       ______________________________________                                    

The emulsion was then tested by the streak test method. The results were reported as the range of concentration of Oxazolidine A, between which growth is allowed and complete inhibition is achieved, for the organisms listed.

    ______________________________________                                                           Inhibiting                                                                     Concentration                                                ______________________________________                                         BACTERIA                                                                       Staphylococcus aureus                                                                              100 - 500 μg/ml                                         Streptococcus fecalis                                                                              100 - 500                                                  Streptococcus hemolyticus                                                                          100 - 500                                                  Escherichia coli    100 - 500                                                  Pasteruella pseudotuberculosis                                                                      50 - 100                                                  Pseudomonas aeruginosa                                                                             100 - 500                                                  Shigella dysenteriae                                                                                10 - 50                                                   Mycobacterium tuberculosis                                                                         100 - 500                                                  FUNGI                                                                          A. niger            500 - 1000 μg/ml                                        Candida Albicans    1000                                                       Penicillium species 100 - 500                                                  A. Fumigatus        100 - 500                                                  ______________________________________                                    

EXAMPLE 3

The object of the following experiment was to determine the concentration of Oxazolidine A required to prevent attack by soil organisms on a starch-based drilling mud.

A starch solution, simulating a starch-based drilling mud, was prepared by dispersing 100 g of starch in 150 g of deionized water, then diluting with 2000 g of deionized water. Aliquots of 200 g each of this solution were then delivered to 4 oz. jars.

A suspension of soil organisms was prepared by extracting 5 g of ordinary soil with 100 ml of water. To the starch solution in each of the 4 oz. jars was added 1 ml of the suspension of soil micro-organisms. The pH was adjusted to 7 and to each of 3 jars there was added sufficient Oxazolidine A to provide a concentration of 0.1%, 0.2% and 0.3%, respectively. The jars were then incubated at 37° C for 96 hours.

After the incubation period, sterile agar plates were inoculated with supernatant liquid from the jars. The plates were then incubated for another 24 hours and results were recorded as growth or no growth. None of the samples treated with Oxazolidine A showed any growth. A control sample without bactericide showed growth.

EXAMPLE 4

The experiment of Example 3 was repeated in all essential details except that one group of samples was adjusted to pH 5 and another to pH 9. No growth was observed in those treated with Oxazolidine A but growth did occur in the controls without bactericide.

EXAMPLE 5

The experiments of Examples 3 and 4 were repeated in all essential details except that 1-aza-5-ethyl-3,7-dioxabicyclo-[3.3.0]-octane (Oxazolidine E) was substituted for Oxazolidine A. At 0.1% concentration, growth occurred at all pH levels. At 0.2% and 0.3% concentrations, no growth occurred regardless of pH.

The experiment of Example 1 was repeated in all essential details except that Oxazolidine E was substituted for A, and algae and viruses were omitted. The compound was effective against the bacteria and two fungi at a concentration of 1000 μg/ml or less as shown in Table 1.

EXAMPLE 6

The experiment of Example 5 was repeated in all essential details except that 1-aza-5-hydroxymethyl-3,7-dioxabicyclo-[3.3.0]-octane (Oxazolidine T) was substituted for Oxazolidine E. Growth occurred at 0.1% concentration at all pH levels but no growth occurred at 0.2% concentration at any pH. Anomalously, at 0.3%, growth occurred at pH 5, but not at pH 7 or 9. The finding at pH 5 is believed to be unreliable but was not checked.

The experiment of Example 1 was repeated in all essential details except that Oxazolidine T was substituted for A and algae and viruses were omitted. The compound was effective against the bacteria and two fungi at a concentration of 1000 μg/ml or less as shown in Table 1.

EXAMPLE 7

The experiment of Example 1 is repeated in all essential details except that 1,3-oxazolidine is substituted for 4,4-dimethyl-1,3-oxazolidine (Oxazolidine A). Inhibition of bacteria, fungi, algae and the virus strains is obtained at concentrations of 10 - 1000 μg/ml.

EXAMPLE 8

N-Methyl-2-amino-2-methyl-1-propanol, 51.5 g (0.45 mole) and 37% formaldehyde 40.5 g (0.46 mole) were mixed and allowed to stand overnight at room temperature. The mixture was then distilled and the fraction obtained at 130° was taken as the product. There was obtained 3,4,4-trimethyl-1,3-oxazolidine. It was effective against bacteria and two fungi at a concentration of 500 μg/ml or less as shown in Table 1.

EXAMPLES 9 - 12

The experiment of Example 1 was repeated in all essential details using bacteria and fungi except that each of the following oxazolidines was tested in place of Oxazolidine A:

Example 9. 4,4-Dimethyl-2-(2-hydroxyphenyl)-1,3-oxazolidine

Example 10. Propionic acid ester of Oxazolidine T

Example 11. 4-Ethyl-1,3-oxazolidine

Example 12. 1-Aza-5-hydroxymethyl-2,8-dimethyl-3,7-dioxabicyclo[3.3.0]-octane*

The results obtained were as follows:

                                      TABLE I                                      __________________________________________________________________________                      GROWTH INHIBITING CONCENTRATION                               EXAMPLE NO.      5 6 8 9 10                                                                               11                                                                               12                                                                               13                                                                               14                                                                               15 16                                                                               18                                     __________________________________________________________________________     BACTERIA                                                                       Staphylococcus aureus                                                                           D D C D C C D C B B  B B                                      Streptococcus fecalis                                                                           C D C E C C C C B B  B C                                      Streptococcus hemolyticus                                                                       D D D E C C D C B B  B B                                      Escherichia coli E D D C E C D C B B  B B                                      Pasteurella pseudotuberculosis                                                                  B D C C C C C B A AA A A                                      Pseudomonas aeruginosa                                                                          E D D D E C D C B D  B B                                      Shigella dysenteriae                                                                            D D C D C C D C B D  B B                                      Mycobacterium tuberculosis                                                                      D D D --                                                                               C C C C A -- A B                                      FUNGI                                                                          A. Niger         E E D B E D E C A A  A B                                      Candida albicans E E E B E E E D A A  A B                                      Penicillium species                                                                             D B D B E C E C A A  A A                                      A fumigatus      D B D B E C E C A A  A A                                      __________________________________________________________________________      AA=1-10 μg/ml                                                               A=10-50 μg/ml                                                               B=50-100 μg/ml                                                              C=100-500 μg/ml                                                             D=500-1000 μg/ml                                                            =>1000 μg/ml                                                          

EXAMPLE 13

2-Nitropropane 89 g (1 mole) and 37% formaldehyde 88 g (1 mole) were mixed together and heated to 65° C. There was then added dropwise Oxazolidine A 101 g (1 mole) and after the addition was complete, heating of the reaction mixture at 60°-70° C was continued for 2 hours. Water was then removed by distillation at about 8-12 mm Hg pressure. There was obtained N-(2-methyl-2-nitropropyl)-4,4-dimethyl-1,3-oxazolidine. It analyzed carbon 53.65% (calc. 53.47), hydrogen 9.07% (calc. 8.98) and nitrogen 13.47% (calc. 13.87). The compound was effective against bacteria and fungi at a concentration of 500 μg/ml or less as shown in Table 1.

EXAMPLE 14

The experiment of Example 13 was repeated in all essential details except that 1-nitropropane was substituted for 2-nitropropane. There was obtained N-(2-nitrobutyl)-4,4-dimethyl-1,3-oxazolidine. It was effective against bacteria and fungi at a concentration of 100 μg/ml or less as shown in Table 1.

EXAMPLE 15

The experiment of Example 14 was repeated in all essential details except that 2 moles of formaldehyde were substituted for 1 mole. There was obtained N-3-(2-ethyl-2-nitro-1-propanol)-4,4-dimethyl-1,3-oxazolidine. The compound was effective against bacteria and fungi at a concentration of 100 μg/ml or less as shown in Table 1.

EXAMPLE 16

1-Nitropropane, 89 g (1 mole) 37% formaldehyde, 162 g (2 moles), were mixed and heated to 60°-70° C. Oxazolidine A, 253 g (2 moles) was added dropwise and after addition was complete, heating was continued for 2 hours. The solution was then distilled at reduced pressure to remove water. There was obtained 250 g of residue having a neutral equivalent of 204.1. It was determined to be 2-nitro-2-ethyl-1,3-bis(4,4-dimethyl-1,3-oxazolidinyl)-propane. It was effective against both bacteria and fungi at 100 μg/ml or less as shown in Table 1.

EXAMPLE 17

The experiment of Example 16 is repeated in all essential details except that nitroethane, (1 mole), is substituted for 1-nitropropane. There is obtained 2-nitro-2-methyl-1,3-bis(4,4-dimethyl-1,3-oxazolidinyl)-propane. It is effective against both bacteria and fungi.

EXAMPLE 18

Nitroethane 102 g (1.36 moles) was mixed with 37% formaldehyde 211 g (2.6 moles) and 1200 g of water. The temperature was adjusted to 25°-35° C and Oxazolidine A 210 g (2.08 moles) was added dropwise. The mixture was then heated at about 60° C for about 3 hours. The mixture was allowed to cool whereupon crystals separated. They were recovered by filtration, and washed with cold isopropyl alcohol. There was obtained 2-nitro-2-methyl-1,3-bis(4,4-dimethyl-1,3-oxazolidinyl)-propane. It had a neutralization equivalent of 160.9 (calc. 150.5) and a melting point of 107.6°. It was effective against bacteria and fungi as shown in Table I. 

I claim:
 1. A compound represented by the formula ##STR8## wherein R and R¹ are hydrogen or alkyl of 1 or 2 carbon atoms and can be the same or different; R³ is hydrogen, alkyl of from 1 to 3 carbon atoms or hydroxyphenyl; where R⁶ is hydrogen, methyl, or ethyl and R⁷ is methyl, hydroxymethyl, or ethyl.
 2. The composition of claim 1 wherein R⁶ is hydrogen and R⁷ is ethyl.
 3. The composition of claim 1 wherein R⁶ and R⁷ are methyl.
 4. The composition of claim 1 wherein R⁶ is ethyl and R⁷ is hydroxymethyl. 